The overall goal of this proposal is to develop peripherally selective cannabinoid receptor 1 (CB1R) antagonists to treat hepatic fibrosis. The endocannabinoid system (EC) has emerged over the years as a key regulator of hepatic diseases. There are two accepted EC receptors - CB1R and CB2R. They are expressed in the central nervous system (CNS) and certain peripheral tissues. While these GPCRs are marginally expressed in the normal liver, they are up-regulated upon injury or disease. Functional studies indicate that CB1R and CB2R have opposing roles in liver fibrosis. While CB1R activation is pro-fibrotic, CB2R activation is anti-fibrotic. Accordingly, genetic or pharmacological blockade of CB1R has been demonstrated to inhibit liver disease in various preclinical models and the receptor is a target for medications development. Unfortunately, non-tissue-selective antagonists of CB1R produce adverse psychiatric effects in humans and are not suitable for chronic use. However, emerging preclinical evidence suggests that targeting peripherally expressed CB1R is an exciting new strategy for treating hepatic and metabolic disorders. Our group has been successfully involved in the development of peripherally selective CB1R antagonists over the last couple of years having produced CB1R compounds that have <7% penetration into the CNS, have ~10 nM potency, are >50-fold selectivity for CB1R over CB2R, and are orally absorbed with reasonable half-lives. It is expected that further refinement of these antagonists through this R01 application will produce compounds for IND-enabling studies. Four specific aims are proposed. Through aim 1, refinement of a diphenyl-purine CB1R antagonist scaffold will continue to produce compounds that have even lower CNS-penetration (<2%). Through aim 2, these compounds will be pharmacologically characterized in vitro to determine their potency, selectivity, toxicity, and metabolic stability. Selected compounds will be tested in vivo to establish their pharmacokinetic (PK) profile and to rule out antagonism of central CB1R using a battery of behavioral tests. Through aim 3, candidate compounds will be tested for efficacy in two well-established models of liver fibrosis for abrogation of disease progression. Several phenotypic and molecular disease-relevant biomarkers will be evaluated as well to evaluate degree of efficacy. Through aim 4, advanced lead compounds will be tested in a behavioral rodent forced-swim assay to identify any potential psychiatric adverse effects induced by chronic dosing. Taken together, successful completion of the project will produce novel compounds for clinical development to treat hepatic fibrosis, which is an area of urgent need.